Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?

BACKGROUND: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC. METHODS: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS. RESULTS: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98). CONCLUSIONS: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.

Predictors of Morbidity and Mortality After Colorectal Surgery in Patients With Cirrhotic Liver Disease-A Retrospective Analysis of 54 Cases at a Tertiary Care Center.

Background: Despite various existing scores that predict morbidity and mortality of patients with cirrhotic liver disease (CLD), data on specific risk stratification of patients with CLD undergoing colorectal surgery (CRS) are rare. The aim of this study was to assess in-hospital morbidity and mortality of patients with liver cirrhosis scheduled for CRS, with specific focus on possible pitfalls of surgery in this special cohort. Methods: Between 1996 and 2018, 54 patients with CLD undergoing CRS were identified and included in this study cohort. Postoperative morbidity and mortality were assessed using the Clavien/Dindo (C/D) classification as well as by type of complication. Univariate and multivariate analyses were performed to analyze the predictive factors for increased postoperative morbidity. Results: Of the patients, 37% patients died during the procedure or postoperatively. Major complications were seen in 23.1% of patients (>C/D IIIb). Patients with Child B or C cirrhosis as well as patients undergoing emergency surgery experienced significantly more major complications (p = 0.04 and p = 0.023, respectively). The most common complications were bleeding requiring blood transfusion (51.1%) and cardiocirculatory instability due to bleeding or sepsis (44.4%). In 53.7% of patients, an anastomosis was created without a protective ostomy. Anastomotic leakage occurred in 20.7% of these patients. Multivariate analysis showed that a primary anastomosis without a protective ostomy was the strongest risk factor for major complications (p = 0.042). Discussion: Morbidity and mortality after CRS in patients with CLD remains high and is not only influenced by liver function but also by surgical variables. Considering the high rate of anastomotic leakage, creating a protective or definitive ostomy must be considered with regard to the underlying pathology, the extent of CLD, and the patient's condition. Moreover, our data suggest that surgery in these most fragile patients should be performed only in experienced centers with immediate contact to hepatologists and experts in hemostasis.

Surgical treatment of mechanical bowel obstruction: characteristics and outcomes of geriatric patients compared to a younger cohort.

PURPOSE: Mechanical bowel obstruction (MBO) is one of the most common indications for emergency surgery. Recent research justifies the method of attempting 3-5 days of nonoperative treatment before surgery. However, little is known about specific characteristics of geriatric patients undergoing surgery compared to a younger cohort. We aimed to analyze patients with MBO that required surgery, depending on their age, to identify potential targets for use in the reduction in complications and mortality in the elderly. METHODS: Thirty-day and in-hospital mortality were determined as primary outcome. We retrospectively identified all patients who underwent surgery for MBO at the University Hospital of Bonn between 2009 and 2019 and divided them into non-geriatric (40-74 years, n = 224) and geriatric (≥ 75 years, n = 88) patients, using the chi-squared-test and Mann-Whitney U test for statistical analysis. RESULTS: We found that geriatric patients had higher 30-day and in-hospital mortality rates than non-geriatric patients. As secondary outcome, we found that they experienced a longer length of stay (LOS) and higher complication rates than non-geriatric patients. Geriatric patients who suffered from large bowel obstruction (LBO) had a higher rate of bowel resection, stoma creation, and a higher 30-day mortality rate. The time from admission to surgery was not shown to be crucial for the outcome of (geriatric) patients. CONCLUSION: Geriatric patients suffering from mechanical bowel obstruction that had to undergo surgery had higher mortality and morbidity than non-geriatric patients. Especially in regard to geriatric patients, clinicians should treat patients in a risk-adapted rather than time-adapted manner, and conditions should be optimized before surgery.

Transcutaneous vagal nerve simulation to reduce a systemic inflammatory response syndrome and the associated intestinal failure: study protocol of a prospective, two-armed, sham-controlled, double-blinded trial in healthy subjects (the NeuroSIRS-Study).

PURPOSE: Surgery initiates pro-inflammatory mediator cascades leading to a variably pronounced sterile inflammation (SIRS). SIRS is associated with intestinal paralysis and breakdown of intestinal barrier and might result in abdominal sepsis. Technological progress led to the development of a neurostimulator for transcutaneous auricular vagal nerve stimulation (taVNS), which is associated with a decline in inflammatory parameters and peristalsis improvement in rodents and healthy subjects via activation of the cholinergic anti-inflammatory pathway. Therefore, taVNS might be a strategy for SIRS prophylaxis. METHODS: The NeuroSIRS-Study is a prospective, randomized two-armed, sham-controlled, double-blind clinical trial. The study is registered at DRKS00016892 (09.07.2020). A controlled endotoxemia is used as a SIRS-mimicking model. 2 ng/kg bodyweight lipopolysaccharide (LPS) will be administered after taVNS or sham stimulation. The primary objective is a reduction of clinical symptoms of SIRS after taVNS compared to sham stimulation. Effects of taVNS on release of inflammatory cytokines, intestinal function, and vital parameters will be analyzed. DISCUSSION: TaVNS is well-tolerated, with little to no side effects. Despite not fully mimicking postoperative inflammation, LPS challenge is the most used experimental tool to imitate SIRS and offers standardization and reproducibility. The restriction to healthy male volunteers exerts a certain bias limiting generalizability to the surgical population. Still, this pilot study aims to give first insights into taVNS as a prophylactic treatment in postoperative inflammation to pave the way for further clinical trials in patients at risk for SIRS. This would have major implications for future therapeutic approaches.

Electrical vagus nerve stimulation as a prophylaxis for SIRS and postoperative ileus.

Abdominal surgery results in an activation of immune cells of the bowel wall and a consecutive cytokine and nitric oxide (NO) release leading to an inflammation of the muscularis externa and a bowel paralysis, the so-called postoperative ileus (POI). In addition to the local inflammation, major surgical trauma can also lead to a variable pronounced systemic inflammation up to its maximum variant, the systemic inflammatory response syndrome (SIRS), with hypotension, capillary leak and a breakdown of the intestinal barrier function followed by multi-organ dysfunction (MODS). Until now, neither for SIRS nor for POI, a prophylaxis or an evidence-based treatment exists. Since the pioneering work from Kevin Tracey and his group in the late 90s characterizing the role of the vagus nerve in inflammation and describing the cholinergic anti-inflammatory pathway (CAIP) for the first time, substantial efforts have been made in the research field of neuro-immune interactions. Today, the anti-inflammatory potential of vagus nerve stimulation is moving more and more into focus resulting in new therapeutic approaches. This review focuses on the role of the CAIP in the development of SIRS and POI. Furthermore, new therapeutic options like transcutaneous vagus nerve stimulation are highlighted.

Normothermic Machine Perfusion (NMP) of the Liver - Current Status and Future Perspectives.

A shortage of available organs for liver transplantation has led transplant surgeons and researchers to seek for innovative approaches in hepatoprotection and improvement of marginal allografts. The most exciting development in the past decade has been continuous mechanical perfusion of livers with blood or preservation solution to mitigate ischemia-reperfusion injury in contrast to the current standard of static cold storage. Two variations of machine perfusion have emerged in clinical practice. During hypothermic oxygenated perfusion the liver is perfused using a red blood cell-free perfusate at 2-10°C. In contrast, normothermic machine perfusion mimics physiologic liver perfusion using a red blood cell-based solution at 35.5-037.5°C, offering a multitude of potential advantages. Putative effects of normothermic perfusion include abrogation of hyperfibrinolysis after reperfusion and inflammation, glycogen repletion, and regeneration of adenosine triphosphate. Research in normothermic machine perfusion focuses on development of biomarkers predicting allograft quality and susceptibility to ischemia-reperfusion injury. Moreover, normothermic perfusion of marginal allografts allows for application of a variety of therapeutic interventions potentially enhancing organ quality. Both methods need to be subjected to translational investigation and evaluation in clinical trials. A clear advantage is transformation of an emergency procedure at night into a planned daytime surgery. Current clinical trials suggest that normothermic perfusion not only increases the use of hepatic allografts but is also associated with milder ischemia-reperfusion injury, resulting in a reduced risk of early allograft dysfunction and less biliary complications, including ischemic cholangiopathy, compared to static cold storage. The aim of this review is to give a concise overview of normothermic machine perfusion and its current applications, benefits, and possible advances in the future.

Safety and Suitability of the SmartPill® after Abdominal Surgery: Results of the Prospective, Two-Armed, Open-Label PIDuSA Trial.

INTRODUCTION: Postoperative ileus (POI) is a common complication after abdominal surgery. Until today, an evidence-based treatment of prolonged POI is still lacking, which can be attributed to the poor quality of clinical trials. Various different surrogate markers used to define POI severity are considered to be the cause of low-quality trials making it impossible to derive treatment recommendation. The SmartPill®, which is able to record pH values, temperature and pressure after ingestion, could be an ideal tool to measure transit times and peristalsis and therefore analyze POI severity. Unfortunately, the device has no approval for postoperative use due to safety concerns. The primary objective of the study is to determine safety of the SmartPill® in patients undergoing surgery. Secondary objectives were the quality of the recorded data and the suitability of the SmartPill® for analyzing intestinal motility after different surgical procedures. METHODS: The PIDuSA Study is a prospective, 2-arm, open-label trial. At the end of surgery, the SmartPill® was applied to 49 patients undergoing abdominal surgery having a high risk for impaired intestinal motility and 15 patients undergoing extra-abdominal surgery. Patients were visited daily to access safety data of the SmartPill® on the basis of adverse and serious adverse events (AEs/SAEs). Suitability and data quality were investigated by analyzing data completeness and feasibility to determine transit times and peristalsis for all sections of the gastrointestinal tract. RESULTS: In total, 179 AEs and 8 SAEs were recorded throughout the study affecting 42 patients in the abdominal (158 AEs) and 9 patients in the extra-abdominal surgery group (21 AEs, p = 0.061); none of them were device related. Primary capsule failure was observed in 5 patients, ultimately resulting in an impossibility of data analysis in only 3 patients (4.4%). 9% of the recorded data were incomplete due to the patient's incompliance in keeping the receiver close to the body. In 3 patients (4.4%), isolated small bowel transit could not be determined due to pH alterations as a result of prolonged POI. DISCUSSION: Our study demonstrates that the use of the SmartPill® is safe after surgery but requires a reasonable patient compliance to deliver meaningful data. An objective analysis of transit times and peristalsis was possible irrespective of type and site of surgery in over 95% indicating that the SmartPill® has the potential to deliver objective parameters for POI severity in future clinical trials. However, in some patients with prolonged POI, analysis of small bowel transit could be challenging.

Risk Factors for Postoperative Morbidity and Mortality after Small Bowel Surgery in Patients with Cirrhotic Liver Disease-A Retrospective Analysis of 76 Cases in a Tertiary Center.

(1) Purpose: As it is known, patients with liver cirrhosis (LC) undergoing colon surgery or hernia surgery have high perioperative morbidity and mortality. However, data about patients with LC undergoing small bowel surgery is lacking. This study aimed to analyze the morbidity and mortality of patients with LC after small bowel surgery in order to determine predictive risk factors for a poor outcome. (2) Methods: A retrospective analysis was performed of all patients undergoing small bowel surgery between January 2002 and July 2018 and identified 76 patients with LC. Postoperative complications were analyzed using the classification of Dindo/Clavien (D/C) and further subdivided (hemorrhage, pulmonary complication, wound healing disturbances, renal failure). A total of 38 possible predictive factors underwent univariate and multivariate analyses for different postoperative complications and in-hospital mortality. (3) Results: Postoperative complications [D/C grade ≥ II] occurred in 90.8% of patients and severe complications (D/C grade ≥ IIIB) in 53.9% of patients. Nine patients (11.8%) died during the postoperative course. Predictive factors for overall complications were "additional surgery" (OR 5.3) and "bowel anastomosis" (OR 5.6). For postoperative mortality, we identified the model of end-stage liver disease (MELD) score (OR 1.3) and portal hypertension (OR 5.8) as predictors. The most common complication was hemorrhage, followed by pulmonary complications, hydropic decompensation, renal failure, and wound healing disturbances. The most common risk factors for those complications were portal hypertension (PH), poor liver function, emergency or additional surgery, ascites, and high ASA score. (4) Conclusions: LC has a devastating influence on patients' outcomes after small bowel resection. PH, poor liver function, high ASA score, and additional or emergency surgery as well as ascites were significant risk factors for worse outcomes. Therefore, PH should be treated before surgery whenever possible. Expansion of the operation should be avoided whenever possible and in case of at least moderate preoperative ascites, the creation of an anastomotic ostomy should be evaluated to prevent leakages.